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A water-soluble magnetic resonance imaging (MRI) contrast agent, Dextran mono-N-succinimidyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate-gadolinium(3+) (Dex-DOTA-Gd(3+)), was shown to enable monitoring of the anatomical migration and the survival period of transplanted stem cells for up to 1 month. Gadolinium molecules in the cells were rapidly eliminated from the site and excreted upon cell death. Endothelial progenitor cells (EPCs) transplanted into the inguinal femoral muscle of rats migrated distally through the knee in rats after hindlimb ischemia but did not migrate in non-ischemic rats. Interestingly, the survival period of transplanted EPCs was notably prolonged in the ischemic limb, indicating that EPCs are required by the ischemic tissues and that the fate of transplanted EPCs was affected by the disease. Compared to the commonly used particle type of MRI contrast agents, the system described in this study is expected to be invaluable to help clarifying the process of stem cell transplantation therapy.

Contains fulltext : 81484.pdf (Publisher’s version ) (Closed access) Spinal cord injury (SCI) results in loss of nervous tissue and consequently loss of motor and sensory function. There is no treatment available that restores the injury-induced loss of function to a degree that an independent life can be guaranteed. Transplantation of stem cells or progenitors may support spinal cord repair. Stem cells are characterized by self-renewal and their ability to become any cell in an organism. Promising results have been obtained in experimental models of SCI. Stem cells can be directed to differentiate into neurons or glia in vitro, which can be used for replacement of neural cells lost after SCI. Neuroprotective and axon regeneration-promoting effects have also been credited to transplanted stem cells. There are still issues related to stem cell transplantation that need to be resolved, including ethical concerns. This paper reviews the current status of stem cell application for spinal cord repair.

Contains fulltext : 51311.pdf (Publisher’s version ) (Open Access) Stem cells have been recognized and intensively studied for their potential use in restorative approaches for degenerative diseases and traumatic injuries. In the central nervous system (CNS), stem cell-based strategies have been proposed to replace lost neurons in degenerative diseases such as Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (Lou Gehrig's disease), or to replace lost oligodendrocytes in demyelinating diseases such as multiple sclerosis. Stem cells have also been implicated in repair of the adult spinal cord. An impact to the spinal cord results in immediate damage to tissue including blood vessels, causing loss of neurons, astrocytes, and oligodendrocytes. In time, more tissue nearby or away from the injury site is lost due to secondary injury. In case of relatively minor damage to the cord some return of function can be observed, but in most cases the neurological loss is permanent. This review will focus on in vitro and in vivo studies on the use of bone marrow stromal cells (BMSCs), a heterogeneous cell population that includes mesenchymal stem cells, for repair of the spinal cord in experimental injury models and their potential for human application. To optimally benefit from BMSCs for repair of the spinal cord it is imperative to develop in vitro techniques that will generate the desired cell type and/or a large enough number for in vivo transplantation approaches. We will also assess the potential and possible pitfalls for use of BMSCs in humans and ongoing clinical trials.

Bone marrow stromal cell (BMSC) transplantation has shown promise for repair of the spinal cord. We showed earlier that a BMSC transplant limits the loss of spinal nervous tissue after a contusive injury. Here, we addressed the premise that BMSC-mediated tissue sparing underlies functional recovery in adult rats after a contusion of the thoracic spinal cord. Our results reveal that after 2 months BMSCs had elicited a significant increase in spared tissue volumes and in blood vessel density in the contusion epicenter. A strong functional relationship existed between spared tissue volumes and blood vessel density. BMSC-transplanted rats exhibited significant improvements in motor, sensorimotor, and sensory functions, which were strongly correlated with spared tissue volumes. Retrograde tracing revealed that rats with BMSCs had twice as many descending brainstem neurons with an axon projecting beyond the contused spinal cord segment and these correlated strongly with the improved motor/sensorimotor functions but not sensory functions. Together, our data indicate that tissue sparing greatly contributes to BMSC-mediated functional repair after spinal cord contusion. The preservation/formation of blood vessels and sparing/regeneration of descending brainstem axons may be important mediators of the BMSC-mediated anatomical and functional improvements.

Contains fulltext : 89439.pdf (Publisher’s version ) (Closed access) Spinal cord injury (SCI) results in loss of nervous tissue in the spinal cord and consequently loss of motor and sensory function. The impairments are permanent because endogenous repair events fail to restore the damaged axonal circuits that are involved in function. There is no treatment available that restores the injury-induced loss of function. The consequences of SCI are devastating physically and socially. The assessment of functional loss after SCI has been standardized in the larger part of the world. For medical care however there are no standards available. During the early phase, treatments that stabilize the patient's health and attempt to limit further neurological deterioration need to be implemented. During the later phase of SCI, the focus needs to be on prevention and/or treatment of secondary complications such as pain, pressure ulcers, and infections. Neuroprotective, axon growth-promoting and rehabilitative repair approaches are currently being tested but, so far, none of these has emerged as an effective treatment that reverses the consequences of SCI. Promising new repair approaches have emerged from the laboratory during the last years and entered the clinical arena including stem cell transplantation and functional electrical stimulation.

This study was initiated due to an NIH “Facilities of Research - Spinal Cord Injury” contract to support independent replication of published studies. Transient blockage of the CD11d/CD18 integrin has been reported to reduce secondary neuronal damage as well as to improve functional recovery after spinal cord injury (SCI) in rats. The purpose of this study was to determine whether treatment with an anti-CD11d monoclonal antibody (mAb) would improve motor performance, reduce pain and histopathological damage in animals following clip-compression injury as reported. Adult male Wistar rats (250 g) were anesthetized with isoflurane, and the T12 spinal cord exposed by T10 and T11 dorsal laminectomies followed by a 60 second period of clip compression utilizing a 35 gram clip. Control animals received an isotype-matched irrelevant antibody (1B7) while the treated group received the anti-CD11d mAb (217L; 1.0 mg/kg) systemically. Open-field locomotion and sensory function were assessed and animals were perfusion-fixed at twelve weeks after injury for quantitative histopathological analysis. As compared to 1B7, 217L treated animals showed an overall non-significant trend to better motor recovery. All animals showed chronic mechanical allodynia and anti-CD11d mAb treatment did not significantly prevent its development. Histopathological analysis demonstrated severe injury to gray and white matter after compression with a non-significant trend in anti-CD11d protection compared to control animals for preserved myelin. Although positive effects with the anti-CD11d mAb treatment have been reported after compressive SCI, it is suggested that this potential treatment requires further investigation before clinical trials in spinal cord injured patients are implemented.

Item does not contain fulltext We investigated whether small-animal positron emission tomography (PET) could be used in combination with computed tomography (CT) imaging techniques for longitudinal monitoring of the injured spinal cord. In adult female Sprague-Dawley rats (n = 6), the ninth thoracic (T9) spinal cord segment was exposed by laminectomy and subsequently contused using the Infinite Horizon impactor (Precision System and Instrumentation, Lexington, KY) at 225 kDyn. In control rats (n = 4), the T9 spinal cord was exposed by laminectomy but not contused. At 0.5 hours and 3, 7, and 21 days postinjury, 2-[(18)F]fluoro-2-deoxy-d-glucose ([(18)F]FDG) was given intravenously followed 1 hour later by sequential PET and CT. Regions of interest (ROIs) at T9 (contused) and T6 (uninjured) spinal cord segments were manually defined on CT images and aided by fiduciary markers superimposed onto the coregistered PET images. Monte Carlo simulation revealed that about 33% of the activity in the ROIs was due to spillover from adjacent hot areas. A simulation-based partial-volume compensation (PVC) method was developed and used to correct for this spillover effect. With PET-CT, combined with PVC, we were able to serially measure standardized uptake values of the T9 and T6 spinal cord segments and reveal small, but significant, differences. This approach may become a tool to assess the efficacy of spinal cord repair strategies. 01 april 2010

Until recently, the bronchial circulation has been relatively ignored in the research and clinical arenas, perhaps because of its small volume and seeming dispensability relative to the pulmonary circulation. Although the bronchial circulation only receives around 1% of the cardiac output in health, it serves functions that are critical to maintaining airway and lung function. The bronchial circulation also plays an important role in many lung and airway diseases; through its ability to increase in size, the bronchial circulation is able to provide lung parenchymal perfusion when the pulmonary circulation is compromised, and more recently the role of the bronchial circulation in the pathogenesis of inflammatory airway disease has been explored. Due to the anatomic variability and small volume of the bronchial circulation, much of the research to date has necessitated the use of animal models and invasive procedures. More recently, non-invasive techniques for measuring bronchial blood flow in the mucosal microvascular network have been developed and offer a new avenue for the study of this circulation in humans. In conjunction with molecular research, measurement of airway blood flow (Q(aw)) may help elucidate the role of the bronchial circulation in inflammatory airway disease and become a useful tool for monitoring therapy.

Contains fulltext : 80699.pdf (Publisher’s version ) (Open Access) Bone marrow stromal cells (BMSC) transplanted into the contused spinal cord may support repair by improving tissue sparing. We injected allogeneic BMSC into the moderately contused adult rat thoracic spinal cord at 15 min (acute) and at 3, 7, and 21 days (delayed) post-injury and quantified tissue sparing and BMSC survival up to 4 weeks post-transplantation. BMSC survival within the contusion at 7 days post-transplantation was significantly higher with an acute injection (32%) and 3-day delayed injection (52%) than with a 7- or 21-day delayed injection (9% both; p < 0.01). BMSC survival at 28 days post-transplantation was close to 0 in all paradigms, indicating rejection. In contused rats without a BMSC transplant (controls), the volume of spared tissue gradually decreased until 46% (p < 0.001) of the volume of a comparable uninjured spinal cord segment at 49 days post-injury. In rats with BMSC, injected at 15 min, 3, or 7 days post-injury, spared tissue volume was significantly higher in grafted rats than in control rats at the respective endpoints (i.e., 28, 31, and 35 days post-injury). Acute and 3-day delayed but not 7- and 21-day delayed injection of BMSC significantly improved tissue sparing, which was strongly correlated (r = 0.79-1.0) to BMSC survival in the first week after injection into the contusion. Our data showed that neuroprotective effects of BMSC transplanted into a moderate rat spinal cord contusion depend strongly on their survival during the first week post-injection. Acutely injected BMSC elicit more tissue sparing than delayed injected BMSC.

The transplantation of Schwann cells (SCs) and olfactory ensheathing glia (OEG) have shown promise as therapeutic interventions for spinal cord injury (SCI) repair. The current study sought to identify novel sites of transplantation for these glial cells, as opposed to direct intraspinal cord injection, that would be less surgically invasive while permitting their migration to the location of SCI where they could facilitate repair. Adult female Fischer rats first received a moderate contusion of the thoracic (T8) spinal cord. One week later, cultured SCs and OEG, previously ex vivo transduced with lentiviral vectors encoding green fluorescent protein (GFP) to allow their identification, were transplanted by injection (6×105 in media) into the following regions: the (i) injury epicenter, (ii) sub-dural space above the injury site, (iii) dorsal artery immediately rostral to the injury site, (iv) cisterna magna and, (v) lumbar sac. An additional strategy sought to utilize migration of endogenous SCs from the periphery into the injury site, by transducing them through direct injection of lentiviral-GFP into (vi) the dorsal roots innervating the injured spinal cord segment. A 2.5 cm segment of the spinal cord encompassing the injury epicenter was evaluated 10 days post-injection for migration of GFP+ glia to the injury site. Very few GFP-OEG were observed in the injured spinal cord in all transplantation paradigms, indicating either poor survival or migration. Similar results were also obtained with SCs, after transplantation into the cisterna magna, lumbar sac or into the sub-dural space above the injury site. However, transplantation of SC into the dorsal artery did allow modest migration to the injury site, though cell numbers were significantly less in comparison to direct intraspinal cord injection. A substantial number of GFP-SCs were observed within the dorsal columns and dorsal horn following transduction of the dorsal roots; from which they had probably they had migrated. As a control, direct injection of lentiviral-GFP into the injured spinal cord resulted in very little cellular transduction. In conclusion, harnessing the migratory response of endogenous SCs appeared to be the most efficacious of the alternative cellular delivery approaches examined and opens a new possibility for combinatory cellular and gene therapy for SCI repair. (ISRT; CRPF; The Miami Project to Cure Paralysis; NIH/NINDS # 09923)